The primary focus of my work has been to understand the mechanisms by which cancers subvert normal developmental and stem cell signals to grow, spread and evade therapy. In my effort to develop a full view of the signals that regulate stem cell fate I have used molecular, cellular and genetic approaches and pioneered the development of new tools for visualizing molecular signals in living cells, as well as innovative new methods for high resolution in vivo imaging of cancer growth and progression. Over the last decade our work has ranged from discovery of new signals involved in cancer growth and progression to preclinical work that has formed the basis of clinical trials testing new agents for drug-resistant leukemias. Recently, based on our discoveries, we have partnered with industry to develop new antagonists that could be of broad use in many deadly cancers. I have consistently moved my work in new directions, taken risks and crossed disciplines to explore critical questions in cancer biology, developed innovative strategies to address these questions, and worked to translate these findings to the development of new approaches to target cancer. Our prior studies have collectively set the stage for new avenues of research we will pursue over the course of the next few years. In particular we plan to 1) Use our understanding of the conversion from a benign to malignant phase to develop new interventions that will prevent or block cancer progression, 2) develop new tools to image cancer heterogeneity and identify driver population that may mediate disease relapse, 3) spatially map drug resistant residual disease and develop locoregional targeting strategies and 4) develop and test deliverable molecular sensors for early detection.